Germline mutations of the phosphatase and tensin homolog (PTEN) gene (UCSC ID, uc001kfb.2; RefSeq, NM_000314), encoding deletions on chromosome 10, cause 25% of autosomal-dominant Cowden syndrome which minimally occur in 1 in 200,000 live births. These mutations result in a syndrome characterized by macrocephaly and typical mucocutaneous features (trichilemmomas, papillomatous papules) and hamartomas, with increased risk of various malignancies, approximately 28% lifetime risk for thyroid cancer, and as much as 50% lifetime risk for female breast cancer over the general population.
However, only 5% of this heterogeneous group referred to as having Cowden-like syndrome and who have some features of Cowden syndrome but do not meet diagnostic criteria, have germline PTEN mutations. In the absence of germline PTEN mutations, approximately 10% of individuals with Cowden syndrome or Cowden-like syndrome harbor germline succinate dehydrogenase variants SDHB and SDHD. Overall, germline PTEN mutations and deletions and SDHx variants account for 35% of Cowden syndrome and 6% to 11% of individuals with Cowden-like syndrome phenotypic features.
Cowden syndrome is a great clinical mimic and is difficult to recognize because every patient shows variable expression and penetrance. Importantly, many individuals in the general population share one or more features of Cowden syndrome but may not have Cowden syndrome and may not even harbor alterations in any predisposition genes. Many such patients present to primary care and other specialty clinicians who are called upon to recognize such individuals because individuals with specific gene mutations have increased risks of different spectra of neoplasias.
Somatic alterations of CpG island DNA hypermethylation and chromatin modification have been widely documented in human cancers. Jones et al., Cell, 128, 683-692 (2007). Regions in which CpG are exceptionally integrated are known as CpG islands. The CpG islands refer to sites which are 0.2-3 kb in length, and have a C+G content of more than 50% and a CpG ratio of more than 3.75%. There are about 45,000 CpG islands in the human genome, and they are mostly found in promoter regions regulating the expression of genes. In the case of genes whose mutations are attributed to the development of cancer in congenital cancer but do not occur in acquired cancer, the germline methylation of promoter CpG islands occurs instead of mutation. Typical examples include the promoter germline methylation of genes, such as acquired renal cancer VHL (von Hippel Lindau), breast cancer BRCA1, colorectal cancer MLH1, and stomach cancer E-CAD.
DNA methylation changes are not only detectable in tumors, but also in blood, as tumor-derived DNA is released into the bloodstream due to tumor necrosis and apoptosis. Cancer-specific DNA methylation alterations present in cancer tissues and blood of cancer patients can serve as diagnostic markers for risk assessment, progression, early detection, treatment prediction and monitoring. Laird, P. W., Nat Rev Cancer, 3, 253-266 (2003).
In the context of a difficult-to recognize syndrome, identification of additional cancer predisposition genes would facilitate molecular diagnosis, genotype-specific predictive testing of family members who are as yet clinically unaffected, genetic counseling, and medical management. Relevant to primary care, once a mutation or alteration is found, primary care physicians must have a basic understanding of gene-specific cancer risks as they do play and will increase their role as coordinators of gene-specific personalized management, surveillance, and other related factors of care.